The turnover of cardiomyocytes is low in the adult heart but can increase during ischemia through upregulation of Islet-1 positive (Isl1+) or C-Kit positive (C-Kit+) multipotent cardiac progenitor cells (Genead et al., PlosOne 7, e36804 (2012)). The upregulation of endogenous progenitor cells is not sufficient to replace the damaged musculature after substantial ischemic damage, resulting in heart failure. An attractive approach to prevent the development of heart failure would be to provide progenitor cells capable of repairing tissue damage in the heart. These progenitor cells should be capable of giving rise to cardiomyocytes, smooth muscle cells, nerve cells and endothelium. Isl1+ cells have this capacity and form ⅔ of the developing heart including the sino-atrial node (SA), part of the atrial-ventricular node (AV), right atrium, right ventricle, proximal aorta, trunk of the pulmonary arteries and proximal parts of the coronary arteries (Lam et al., Pediatr. Cardiol. 30, 690 (2009)).
However, one considerable limitation in using these progenitor cells for regenerative medicine pertains to the difficulty of expanding well-characterized clonal progenitor cell populations, from either adult human tissue or from fetal/embryonic stem cell tissues. In an earlier study, Laugwitz and coworkers showed that it was possible to expand postnatal Isl1+ cells from transgenic mice if they were co-cultured with cardiac mesenchymal feeder cells (Laugwitz et al., Nature 433, 647 (2005)).
Therefore there is great need in the art for methods that efficiently enable the formation of cardiovascular progenitors and maintaining and expanding these cardiovascular progenitors in a multipotent state to enable the generation of a diverse set of heart lineages. A desired method would enable the production of, and subsequent unlimited expansion of progenitors capable of entering different cardiac lineages. Such a method is highly desirable as it will circumvent many of the issues relating to tissue rejection commonly associated with transplantation therapies, and overall provide alternative regenerative medicine strategies and improve treatment outcomes for patients suffering from a variety of cardiac and cardiovascular disorders.